The critical importance of two-way communication between the brain and the heart during thought, emotion, and behavior has been known for over 100 years, but this knowledge had little impact on alcohol use disorder (AUD) treatment .This revised K24 application by a mid-career translational clinical scientist addresses this gap by translating a new model of neurocardiac signaling (called the baroreflex [BAR] model) into behavioral interventions for AUDs. The research goal is to refine and test interventions based on her basic research supporting the BAR as an active behavioral change mechanism. Interventions that affect the BAR mechanism increase feedback between the brain and cardiovascular system. The overarching hypothesis of this K24 is that enhancing BAR functioning will increase behavioral flexibility towards alcohol as evidenced by reduced drinking, relapse prevention, decreased depression, and other positive psychosocial outcomes. The first specific aim is to use data from four ongoing clinical trials to evaluate the efficacy of two established (aerobic exercise, meditation) and one new (heart rate variability biofeedback) intervention and determine whether the BAR is a common mechanism of action in each intervention. The second aim is to examine whether treatment responders show different patterns of neural connectivity compared to those who do not respond. The third exploratory aim is to build prognostic models using clinical, cardiovascular, and neural indicators to predict which persons are most likely to benefit from interventions that target the BAR mechanism. Whether genetic indicators can improve prediction will also be explored the career development goal is to move the Candidate's patient oriented research program from early to late stage clinical translation. Training aims are to gain expertise in the design, conduct, and analysis of randomized clinical trials, the use of neuroimaging and neurocardiac tools to differentiate treatment responders versus non-responders, and the application of nonlinear sensitivity and uncertainty analysis to build a multi-level prognostic model. The proposed research and career development strategy will provide a unique training opportunity for five rising junior faculty and one graduate student with shared interests in translational clinical science, emotion regulation, and alcohol use disorders. The mentees bring to the team unique backgrounds and collaborations in the clinical psychopathology of emotional dysregulation and interpersonal violence, psychophysiology and exercise science, neuroimaging, and genetics. Attainment of research and training milestones will be gauged formally from yearly conference presentations, peer-reviewed publications, and patient-oriented research grant submissions.